Department of Clinical Neurophysiology, Portsmouth Hospitals NHS Trust, Portsmouth , United Kingdom.
Aston University , Birmingham , United Kingdom.
J Neurophysiol. 2019 Jun 1;121(6):2061-2070. doi: 10.1152/jn.00464.2018. Epub 2019 Mar 27.
Length-dependent peripheral neuropathy typically involves the insidious onset of sensory loss in the lower limbs before later progressing proximally. Recent evidence proposes hyperpolarization-activated cyclic nucleotide-gated (HCN) channels as dysfunctional in rodent models of peripheral neuropathy, and therefore differential expression of HCN channels in the lower limbs was hypothesized as a pathophysiological mechanism accounting for the pattern of symptomatology within this study. We studied six healthy participants, using motor axon excitability including strong and long [-70% and -100% hyperpolarizing threshold electrotonus (TEh)] hyperpolarizing currents to preferably study HCN channel function from the median and tibial nerves from high (40%) and low (20%) threshold. This was recorded at normothermia (32°C) and then repeated during hyperthermia (40°C) as an artificial hyperpolarizing axon stress. Significant differences between recovery cycle, superexcitability, accommodation to small depolarizing currents, and alterations in late stages of the inward-rectifying currents of strongest (-70% and -100% TEh) currents were observed in the lower limbs during hyperthermia. We demonstrate differences in late current flow, which implies higher expression of HCN channel isoforms. The findings also indicate their potential inference in the symptomatology of length-dependent peripheral neuropathies and may be a unique target for minimizing symptomatology and pathogenesis in acquired disease. This study demonstrates nerve excitability differences between the upper and lower limbs during hyperthermia, an experimentally induced axonal stress. The findings indicate that there is differential expression of slow hyperpolarization-activated cyclic nucleotide-gated (HCN) channel isoforms between the upper and lower limbs, which was demonstrated through strong, long hyperpolarizing currents during hyperthermia. Such mechanisms may underlie postural control but render the lower limbs susceptible to dysfunction in disease states.
长度依赖性周围神经病通常涉及下肢感觉丧失的隐匿性发作，然后再向近端进展。最近的证据表明，超极化激活环核苷酸门控 (HCN) 通道在周围神经病的啮齿动物模型中功能失调，因此，HCN 通道在下肢的差异表达被假设为一种病理生理学机制，解释了该研究中症状模式的原因。我们研究了 6 名健康参与者，使用运动轴突兴奋性，包括强和长 [-70% 和-100% 超极化阈电紧张 (TEh)] 超极化电流，从正中神经和胫神经中优选研究 HCN 通道功能，从高（40%）和低（20%）阈值。这是在常温下（32°C）记录的，然后在高温下（40°C）重复，作为人工超极化轴突应激。在高温下，下肢观察到恢复周期、超兴奋性、对小去极化电流的适应以及最强（-70% 和-100% TEh）电流的内向整流电流晚期的变化之间存在显著差异。我们证明了晚期电流流动的差异，这意味着 HCN 通道同工型的表达更高。这些发现还表明它们可能对长度依赖性周围神经病变的症状学产生潜在影响，并且可能成为最小化获得性疾病中症状学和发病机制的独特目标。 本研究在高温下（一种实验诱导的轴突应激）证明了上肢和下肢之间的神经兴奋性差异。研究结果表明，在上肢和下肢之间存在慢超极化激活环核苷酸门控 (HCN) 通道同工型的差异表达，这是通过在高温下使用强、长的超极化电流来证明的。这种机制可能是姿势控制的基础，但使下肢在疾病状态下易发生功能障碍。
